Polymorphisms in the prion precursor functional gene but not the pseudogene are associated with susceptibility to chronic wasting disease in white-tailed deer

Abstract

Chronic wasting disease (CWD) status and PrP genotypes were determined for a group of 133 wild white-tailed deer in a 780 acre enclosure in western Nebraska, USA. Approximately half of the deer tested showed evidence of PrP d in the brainstem or lymphoid tissues. Four PRNP alleles encoding amino acid substitutions were identified, with substitutions at residues 95 (QRH), 96 (GRS) or 116 (ARG), each with serine (S) at residue 138. In addition, a processed pseudogene with two alleles encoding five or six copies of the octapeptide repeat was identified in 26 % of the deer. Both alleles encoded asparagine (N) at residue 138. The functional gene alleles sorted into five major diploid genotypes and four rare genotypes. Although all five major diploid genotypes were found in deer with CWD, unaffected deer were less likely to have the allele QGAS and more likely to have QSAS compared with CWD-affected deer. Late-stage disease (PrP d in brainstem) was noted in deer less than 1 year of age, although no single genotype was associated with this rapid neuroinvasion. Early-stage disease (PrP d distribution limited to the lymphoid system) was observed in deer estimated to be more than 5 years old, suggesting that they were infected as adults or that the incubation time might be extremely long in some individuals. The pseudogene was found in deer of all major PRNP genotypes and was not correlated with CWD status. The large number of susceptible genotypes and the possibility of adult-to-adult transmission suggest that much of the white-tailed deer population may be at risk for disease following exposure to CWD, despite the association of specific genotypes with CWD noted here.

Influence of the geographic distribution of prion protein gene sequence variation on patterns of chronic wasting disease spread in white-tailed deer (Odocoileus virginianus)

“…A 625 bp region of PRNP that codes amino acids 21 to 227 was amplified by polymerase chain reaction (PCR) using previously published primers CWD-13 and CWD-LA [62] or primers 223 and 224 [37]. Amplification was performed in 25 ul reaction volumes following previously published protocols [34,35,62].…”

“…Sequences were checked for the absence of the aa138N mutation to ensure that all sequences were PRNP and not the processed pseudogene. [38] If aa138N was detected with primers CWD-13 and CWD-LA, then the sequence was verified with primers 223 and 224, which were specifically designed to only amplify the functional gene [37] Though it is possible that this mutation could also occur in the functional gene, we did not observe aa138N in any deer when both primer sets were used.…”

PrPgenetics in ruminant transmissible spongiform encephalopathies

“…The data suggested that the polymorphisms Q95H and G96S reduce the risk of infection. Homozygote SS 96 as well as heterozygote GS 96 and GH 95 deer are underrepresented in CWD-affected populations [55,73]. CWD in mule deer was also shown to have a genetic component with the polymorphism S225F.…”

“…This model assumes uniform exposure of the population to the TSE agent, which may be a special problem when the exposure of free-ranging populations is investigated. Even so, a statistical significant bias in the PrP genotypes between CWD-affected and healthy white-tailed deer has been found in captive [73] and free-ranging populations [55]. The data suggested that the polymorphisms Q95H and G96S reduce the risk of infection.…”

A prion disease of cervids: Chronic wasting disease

“…It is possible, however, that the tg(CerPrP96S) mice may be converted by deer CWD derived from an animal that was SS homozygous at codon 96. In naturally infected white-tailed deer, deer that expressed 96SS PrP had a lower risk for CWD infection, but were not resistant, since at least three of 7350 CWD infected deer were positive for PrP Sc in brain [36,59]. Other studies suggest that the 96S allele delays CWD disease progression [95].…”